Coronary atherogenesis begins before clinically manifest coronary artery disease (CAD) appears. The genesis of arterial plaque composition remain poorly understood. Preclinical coronary artery plaque can be detected using methods, where calcified and uncaicified lesions can be quantified. Known biological pathways associated with stable and unstable "preclinical" arterial plaque in different forms may be elucidated by examining biomarkers from biological pathways and related genes. Gene discovery can be enhanced by examining genome wide associations with plaque morphologic phenotypes detected by computed tomographic (CT) methods. Specifically, we hypothesize that biomarkers and genes related to inflammation, lipid metabolism, cell-signaling, and vascular remodeling have differential effects on calcified and noncalcified plaque morphology. Dr. Krai proposes a study designed to examine "preclinical" forms of arterial plaque in 2 generational kindreds identified from premature CAD probands participating in the 25 year old prospective Johns Hopkins Sibling and Family Heart Study. All subjects have been genotyped for mechanism-driven CAD-related candidate genes and have had a 1 million single nucleotide polymorphism genome-wide association scan (GWAS).The proposed research has these major aims: 1) to determine the extent to which calcified and noncalcified plaque are associated with genotypes or haplotypes from biologically driven models of vascular calcification, vascular function, inflammation, cell-signaling, platelet function, thrombosis, and lipoprotein metabolism, 2) determine the extent to which genetic associations can be accounted for by risk factors and biomarkers, and 3) to determine novel loci associated with the relative total, calcified, and noncalcified plaque volumes using GWAS data. Dr. Krai is a cardiology fellow with a successful history in clinical cardiology research. His long term goal is to develop an independent novel program of genomic and mechanism-derived research directed toward high risk populations, and to improve early detection and attendant preventive therapy. He has assembled a team of senior mentors in genetics, epidemiology, cardiology, and imaging, and will accrue requisite skills in advanced didactic coursework. RELEVANCE (See instructions): Clinical detection of coronary artery plaque calcfication is common practice for risk stratification, although the mechanisms remain unclear. The identification of genes associated with plaque morphology based on biological models or novel genes may have a significant impact on the understanding of atherogenesis and plaque calcification and may lead to tailored diagnostics and therapeutics in preventing CAD events. (End of Abstract)